| Abstract|| |
Background: The clinical profile of dengue fever (DF) is changing and neurological manifestations are being reported more frequently. The exact incidence of various neurological complications is uncertain. Objectives: The aim of this study was to observe the neurological manifestations in dengue infection. Materials and Methods: In this prospective study, 263 confirmed cases of dengue infection were observed for neurological complications. Detailed clinical examination and investigations were done to detect any neurological involvement in dengue infection. Result: In this study, neurological complication was seen in 8.3% (22/263) of patients. The most common neurological manifestation was seizure, seen in 54.54% (12/22) of cases, followed by encephalopathy and meningitis, each of which was seen in 18.18% (4/22) of the cases. The other manifestation was intracerebral hemorrhage, seen in 9.09% (2/22) of cases. Conclusion: The study findings could potentially be explored for a better understanding of neurological complications of dengue infection in endemic areas.
Keywords: Dengue, encephalopathy, meningitis, neurological manifestations of dengue, seizure
|How to cite this article:|
Gupta VK, Lalchandani A, Agrawal K. Neurological manifestations of dengue infection. Ann Trop Med Public Health 2015;8:117-21
|How to cite this URL:|
Gupta VK, Lalchandani A, Agrawal K. Neurological manifestations of dengue infection. Ann Trop Med Public Health [serial online] 2015 [cited 2020 Jul 15];8:117-21. Available from: http://www.atmph.org/text.asp?2015/8/4/117/162370
| Introduction|| |
Dengue infection, an arthropod-borne viral hemorrhagic fever, continues to be a major challenge to public health, especially in Southeast Asia. It has a wide geographical distribution, and can present with a diverse clinical spectrum. It has been estimated that at least 2.5 billion people worldwide live in areas where there is a significant risk of infection from the dengue virus.  Recent observations indicate that the clinical profile of dengue is changing, and that neurological manifestations are being reported more frequently. The exact incidence of various neurological complications is uncertain.  Pathogenesis of the neurological manifestations is multiple and include neurotrophic effect of the dengue virus related to the systemic effects of dengue infection and immune mediated. There are various neurological manifestations including seizure,  encephalopathy,  meningitis, myelitis, Guillain-Barré syndrome (GBS), and myoclonus that are commonly reported.  In the last few years, numerous neurological complications related to dengue fever (DF) have been reported and these lead to significant morbidity and mortality. Neurological complications occur in 0.5-6% of cases with DF.  Systemic complications resulting in encephalopathy, stroke, hypokalemic paralysis, postinfectious immune-mediated acute disseminated encephalomyelitis and myositis have also been reported in some studies. , In dengue endemic countries, it will be prudent to investigate dengue infection in patients with fever and acute neurological manifestations. There is a need to understand the pathogenesis of various neurological manifestations; therefore, we prospectively investigated the neurological manifestations of dengue infection.
| Materials and Methods|| |
Total 263 confirmed cases [based on the World Health Organization (WHO) criteria] of DF were included in this study, who have been admitted in our hospital between August 2011 and October 2014. All the patients of DF presenting with neurological manifestations, admitted in the Department of Medicine were included in this analysis. DF was diagnosed on the basis of the positive serum immunoglobulin M (IgM) antibody and nonstructural protein 1 (NS1) antigen to DF. The serum IgM antibody was analyzed by the enzyme-linked immunosorbent assay (ELISA) method using an IgM antibody capture Elisa (MAC-ELISA, National institute of virology, Pune, India). It was a qualitative analysis and the titers were not measured. The baseline characteristics, including age, sex, occupation, and socioeconomic class, were noted. A detailed history, clinical evaluation, and detailed neurological examination were performed in all the patients. The muscle power was recorded and noted according to the Medical Research Council grading system. Systemic complications of DF including jaundice, lymphadenopathy, hepatosplenomegaly, cardiac failure, gastrointestinal, respiratory, and hematological manifestations were specifically examined. The routine laboratory investigations including hemoglobin level, blood count, platelet estimation, hematocrit, blood sugar, liver function test, renal function test, creatine kinase, prothrombin time, activated partial thromboplastin time, and electrolytes were performed in each patient. The ELISA for human immunodeficiency virus (HIV) was performed in all the patients. Electrocardiogram and chest radiography were done in all the patients. Cerebrospinal fluid (CSF) analysis, and computed tomography (CT) scan and magnetic resource imaging (MRI) of the brain were performed in patients in whom neurological complications were seen.
| Result|| |
Out of the 263 patients, 134 (50.85%) were diagnosed with DF, 121 (46%) with dengue hemorrhagic fever (DHF), and eight (3.16%) with dengue shock syndrome (DSS) based on the WHO criteria. Fever was the manifestation in 100% of the cases, whereas the other most common manifestations were both headache and body ache, presented equally (58.94%), followed by retro-orbital pain seen in 54.37% of the cases. Rash was seen in 27.38% of the cases.
In patients of DF, the other most common manifestation was headache (59.7%), followed by body ache (56.7%), and then retro-orbital pain (50.0%) [Table 1].
|Table 1: Distribution of dengue patients according to the symptoms presented|
Click here to view
In patients of DHF-I, the most common manifestation was mucosal bleed (100% cases) followed by rash (65.85%) followed by myalgia (62.5%), retro-orbital pain (56.25), headache (55.0%), and abdominal pain (53.75%).
In patients of DSS, other most common manifestations were vomiting (75%) followed by headache, myalgia, retro-orbital pain, and abdominal pain. These were present equally in 62.50% of the patients.
Bleeding manifestations were seen in 31.93% of the patients. All the patients (100%) of DHF-II had bleeding, whereas three (37.5%) patients of DSS had bleeding manifestations [Figure 1].
|Figure 1: Distribution of dengue patients according to the symptoms presented|
Click here to view
Seizure was seen in 12 (4.56%) patients, six of them were diagnosed as DF, and the rest as DHF-I.
Hepatomegaly was present in 30.03% of cases, followed by bradycardia (26.23%). Splenomegaly was seen in 24.33% of the cases; 3.04% of the cases were presented as shock and were diagnosed as a case of DSS [Table 2].
Among the patients of DF, bradycardia (30.88%) was the most common sign, followed by splenomegaly (20.15%) and hepatomegaly (15.67%).
Papilledema was seen in eight (3.00%) cases, and all of them had neurological abnormalities. Meningeal signs like neck rigidity and Kernig's signs were positive in four (01.52%) cases, and both of these were under the category of DF. In two (0.76%) cases, focal neurological deficit was seen, which was categorized as DHF. Oliguria was reported in 5.7% of the patients [Figure 2].
Out of the 263 patients, 22 patients (8.3%) had neurological complication. Among them, 70% of the patients can be categorized as those who suffered from classical DF, while 30% of patients suffered from DHF-II [Table 3].
In all the patients of neurological complications, CSF analysis was done; in four patients, cell counts were raised with lymphocytic predominance, sugar was normal, but protein was markedly raised and they were diagnosed as cases of viral meningitis.
The most common neurological manifestation was seizure, seen in 12 patients (4.56%), followed by encephalopathy and meningitis, both seen in 4 patients (1.52%) of DF. In two patients (0.76%), intracranial hemorrhage was seen. None of them were associated with either DHF or DSS.
Meningitis was present in four (1.52%) cases of DF; none of them were associated with either DHF or DSS.
Twelve (4.56%) patients presented as cases of generalized tonic-clonic seizure (GTCS), four of them (1.52%) were having associated encephalopathy, while in eight patients (3.04%) seizure was an independent presentation. Out of the 12 patients presented with seizures, eight (3.04%) were suffering from DF and four patients (1.52%) were diagnosed as cases of DHF [Table 3].
Two patients (0.76%) presented as having an intracranial hemorrhage; these patients presented with focal neurological deficit. Both these cases were diagnosed as DHF [Figure 3].
Risk of neurological complication was more observed in classical DF.
| Discussion|| |
We conducted a prospective study to evaluate the neurological manifestations of dengue infection. In this study, 263 patients of DF were observed for neurological manifestations. In the present study, varied neurological manifestations were observed in association with DF. In this study, we observed that 8.3% (22/263) of patients had neurological complication. The neurological complication in dengue infection has been hypothesized through pathogenic mechanisms concerned with neurotropism, leading to encephalitis, meningitis and myelitis, and systemic complications, thereby resulting in encephalopathy, stroke, and hypokalemic paralysis, and postinfections like immune-mediated acute disseminated encephalomyelitis (ADEM), GBS, and optic neuritis.  Encephalopathy may be due to hyponatremia, cerebral edema, and microvascular frank hemorrhage. The exact incidence and types of neurological manifestations in dengue have not been reported. Various discrete data are available regarding neurological illness in dengue. In a study, neurological manifestation was seen in 0.5-6.2% of patients with DHF and the mortality rate was 22%;  a positive Kernig's sign with meningitis have also been reported in 5.4% of patients with dengue.  Jackson et al. (2008)  reported that 401 cases of suspected viral central nervous system (CNS) infections were investigated for evidence of dengue infection. Frequency of the neurological manifestations of dengue among these CNS cases was found to be 13.5% (54/401). Clinical manifestations among dengue-positive CNS cases included encephalitis in 51.8% (28/54), meningitis in 33.3% (18/54), seizures in 11.1% (6/54), and acute flaccid paralysis/GBS in 3.7% (2/54) of cases. The clinical diagnosis of dengue neurological infection corresponded with laboratory confirmation in 22.2% (12/54) of cases only. Of the cases, 3.7% (2/54) died who had dengue neurological infection.  The patients presented with encephalitis-like illness in DF who may have normal cerebrospinal fluid findings except mildly increased cerebrospinal fluid protein. It can masquerade as other types of acute viral encephalitis. However, its clinical course and prognosis are usually favourable.  Among the neurological manifestation of DF, encephalopathy has been well-reported ,, and has classically been thought to result from the multisystem derangement that occurs in severe dengue infection with liver failure, shock, and coagulopathy, thereby causing cerebral insult. However, there is increasing evidence for dengue viral neurotropism, suggesting that in a proportion of cases, there may be an element of direct viral encephalitis. In the present study, encephalopathy had been seen in a significant number of patients and correlated to other studies. , In the current study, encephalopathy was seen in 18.18% (4/22) of the cases [Table 4]. Another study conducted in 26 patients revealed that 10 were suffering from brachial neuritis, four had encephalopathy, three were consistent with the diagnosis of GBS, three had hypokalemic paralysis associated with DF, and two had acute viral myositis.  Opsoclonus myoclonus syndrome was diagnosed in two patients, myelitis in one, and acute disseminated encephalomyelitis was also diagnosed in one patient. Among the CNS manifestations of DF, seizure is an important symptom presented ,, and it is one of the most common neurological manifestations of DF.  In the current study, seizure was seen in 12/263 patients, and it was most common CNS manifestation (54.5%) [Table 4]. In some studies, epilepsia partialis continua has also been reported as the initial manifestation of dengue.  Meningitis is also a frequently reported CNS manifestation  in DF and meningitis was observed in four patients and it was the second most common manifestation seen (18.18%) in the current study. Meningitis may be an initial presentation in uncomplicated dengue infection.  For the patients who are suffering from viral meningitis, DF may be the etiology in endemic areas. Intracerebral hemorrhage is a fatal neurological manifestation of dengue and this has been reported in few literatures.  In some studies, intracerebral hemorrhage has been seen in 28.6% of cases as neurological complications of dengue infection.  In the current study, intracerebral hemorrhage was seen in 9.09% (2/22) of the cases. Opsoclonus myoclonus syndrome, , acute disseminating encephalomyelitis,  transverse myelitis,  epidural hematoma  and GBS  were reported as rare neurological manifestations in DF; however, these neurological illnesses were not seen in our patients. Hypokalemic periodic paralysis has also been reported in some studies. 
| Conclusion|| |
Although the neurological manifestations are widely reported in dengue infection, detailed exact data are not available. The current study will help to understand the nature and severity of the neurological manifestations of dengue infection in endemic areas.
| Acknowledgement|| |
Department of Radiology and Department of Microbiology, G.S.V.M. Medical College, Kanpur.
| References|| |
Dengue Guidelines for Diagnosis, Treatment, Prevention and Control. 2 nd
ed. Geneva: World Health Organization; 2009. p. 1-144.
Murthy JM. Neurological complication of dengue infection. Neurol India 2010;58:581-4.
Pancharoen C, Thisyakorn U. Neurological manifestations in dengue patients. Southeast Asian J Trop Med Public Health 2001; 32:341-5.
Koley TK, Jain S, Sharma H, Kumar S, Mishra S, Gupta MD, et al
. Dengue encephalitis. J Assoc Physicians India 2003;51:422-3.
Lum LC, Lam SK, Choy YS, George R, Harun F. Dengue encephalitis: A true entity? Am J Trop Med Hyg 1996;54:256-9.
Jackson ST, Mullings A, Bennett F, Khan C, Gordon-Strachan G, Rhoden T. Dengue infection in patients presenting with neurological manifestations in a dengue endemic population. West Indian Med J 2008;57:373-6.
Kankirawatana P, Chokephaibulkit K, Puthavathana P, Yoksan S, Apintanapong S, Pongthapisit V. Dengue infection presenting with central nervous system manifestation. J Child Neurol 2000;15:544-7.
Varatharaj A. Encephalitis in the clinical spectrum of dengue infection. Neurol India 2010;58:585-91.
Verma R, Sharma P, Garg RK, Atam V, Singh MK, Mehrotra HS. Neurological complications of dengue fever: Experience from a tertiary center of north India. Ann Indian Acad Neurol 2011;14:272-8.
Wasay M, Channa R, Jumani M, Shabbir G, Azeemuddin M, Zafar A. Encephalitis and myelitis associated with dengue viral infection clinical and neuroimaging features. Clin Neurol Neurosurg 2008; 110:635-40.
Goswami RP, Mukherjee A, Biswas T, Karmakar PS, Ghosh A. Two cases of dengue meningitis: A rare first presentation. J Infect Dev Ctries 2012;6:208-11.
Angibaud G, Luaute J, Laille M, Gaultier C. Brain involvement in dengue fever. J Clin Neurosci 2001;8:63-5.
Ferreira ML, Cavalcanti CG, Coelho CA, Mesquita SD. Neurological manifestations of dengue: Study of 41 cases. Arq Neuropsiquiatr 2005;63:488-93.
Misra UK, Kalita J, Syam UK, Dhole TN. Neurological manifestations of dengue virus infection. J Neurol Sci 2006;244:117-22.
Solomon T, Dung NM, Vaughn DW, Kneen R, Thao LT, Raengsakulrach B, et al
. Neurological manifestations of dengue infection. Lancet 2000;355:1053-9.
Hendarto SK, Hadinegoro SR. Dengue encephalopathy. Acta Paediatr Jpn 1992;34:350-7.
Verma R, Varatharaj A. Epilepsia partialis continua as a manifestation of dengue encephalitis. Epilepsy Behav 2011;20:395-7.
Wiwanitkit V. Magnitude and pattern of neurological pathology in fatal dengue hemorrhagic fever: A summary of Thai cases. Neuropathology 2005;25:398.
Garg RK, Kar AM, Dixit V. Opsoclonus - myoclonus syndrome in an adult: A case report and response to clonazepam. Indian J Opthamol 1996;44:101-2.
Blaes F, Pike MG, Lang B. Autoantibodies in childhood opsoclonus-myoclonus syndrome. J Neuroimmunol 2008;201-202:221-6.
Sundaram C, Uppin SG, Dakshinamurthy KV, Borgahain R. Acute disseminated encephalomyelitis following dengue hemorrhagic fever. Neurol India 2010;58:599-601.
Leão RN, Oikawa T, Rosa ES, Yamaki JT, Rodrigues SG, Vasconcelos HB, et al
. Isolation of dengue 2 virus from a patient with central nervous system involvement (transverse myelitis). Rev Soc Bras Med Trop 2002;35:401-4.
Singh P, Joseph B. Paraplegia in a patient with dengue. Neurol India 2010;58:962-3.
Soares CN, Cabral-Castro M, Oliveira C, Faria LC, Peralta JM, Freitas MR, et al
. Oligosymptomatic dengue infection: A potential cause of Guillain Barré Syndrome. Arq Neuropsiquiatr 2008; 66:234-7.
Paliwal VK, Garg RK, Juyal R, Husain N, Verma R, Sharma PK, et al
. Acute dengue virus myositis: A report of seven patients of varying clinical severity including two cases with severe fulminant myositis. J Neurol Sci 2011;300:14-8.
Jha S, Ansari MK. Dengue infection causing acute hypokalemic quadriparesis. Neurol India 2010;58:592-4.
Vishal Kumar Gupta
Department of Medicine, GSVM Medical College, Kanpur - 208 002, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4]